Large-Scale Plasma Analysis Revealed New Mechanisms and Molecules Associated with the Host Response to SARS-CoV-2.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to nearly every continent, registering over 1,250,000 deaths worldwide. The effects of SARS-CoV-2 on host targets remains largely limited, hampering our understanding of Coronavirus Disease 2019 (COVID-19) pathogenesis and the development of therapeutic strategies. The present study used a comprehensive untargeted metabolomic and lipidomic approach to capture the host response to SARS-CoV-2 infection. We found that several circulating lipids acted as potential biomarkers, such as phosphatidylcholine 14:0_22:6 (area under the curve (AUC) = 0.96), phosphatidylcholine 16:1_22:6 (AUC = 0.97), and phosphatidylethanolamine 18:1_20:4 (AUC = 0.94). Furthermore, triglycerides and free fatty acids, especially arachidonic acid (AUC = 0.99) and oleic acid (AUC = 0.98), were well correlated to the severity of the disease. An untargeted analysis of non-critical COVID-19 patients identified a strong alteration of lipids and a perturbation of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, aminoacyl-tRNA degradation, arachidonic acid metabolism, and the tricarboxylic acid (TCA) cycle. The severity of the disease was characterized by the activation of gluconeogenesis and the metabolism of porphyrins, which play a crucial role in the progress of the infection. In addition, our study provided further evidence for considering phospholipase A2 (PLA2) activity as a potential key factor in the pathogenesis of COVID-19 and a possible therapeutic target. To date, the present study provides the largest untargeted metabolomics and lipidomics analysis of plasma from COVID-19 patients and control groups, identifying new mechanisms associated with the host response to COVID-19, potential plasma biomarkers, and therapeutic targets.

Bioactive Lipids in COVID-19-Further Evidence.

Previously, I suggested that arachidonic acid (AA, 20:4 n-6) and similar bioactive lipids (BALs) inactivate SARS-CoV-2 and thus, may be of benefit in the prevention and treatment of COVID-19. This proposal is supported by the observation that (i) macrophages and T cells (including NK cells, cytotoxic killer cells and other immunocytes) release AA and other BALs especially in the lungs to inactivate various microbes; (ii) pro-inflammatory metabolites prostaglandin E2 (PGE2) and leukotrienes (LTs) and anti-inflammatory lipoxin A4 (LXA4) derived from AA (similarly, resolvins, protectins and maresins derived from eicosapentaenoic acid: EPA and docosahexaenoic acid: DHA) facilitate the generation of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages respectively; (iii) AA, PGE2, LXA4 and other BALs inhibit interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) synthesis; (iv) mesenchymal stem cells (MSCs) that are of benefit in COVID-19 elaborate LXA4 to bring about their beneficial actions and (v) subjects with insulin resistance, obesity, type 2 diabetes mellitus, hypertension, coronary heart disease and the elderly have significantly low plasma concentrations of AA and LXA4 that may render them more susceptible to SARS-CoV-2 infection and cytokine storm that is associated with increased mortality seen in COVID-19. Statins, colchicine, and corticosteroids that appear to be of benefit in COVID-19 can influence BALs metabolism. AA, and other BALs influence cell membrane fluidity and thus, regulate ACE-2 (angiotensin converting enzyme-2) receptors (the ligand through which SARS-CoV2 enters the cell) receptors. These observations lend support to the contention that administration of BALs especially, AA could be of significant benefit in prevention and management of COVI-19 and other enveloped viruses.